Objective: To analyze the clinical features, efficacy and prognosis factors of core binding factor (CBF) acute myeloid leukemia (AML) children in South China. Methods: This was a retrospective cohort study. Clinical data of 584 AML patients from 9 hospitals between January 2015 to December 2020 was collected. According to fusion gene results, all patients were divided into two groups: CBF-AML group (189 cases) and non-CBF-AML group (395 cases). CBF-AML group were divided into AML1-ETO subgroup (154 cases) and CBFβ-MYH11 subgroup (35 cases). Patients in CBF-AML group chosen different induction scheme were divided into group A (fludarabine, cytarabine, granulocyte colony stimulating factor and idarubicin (FLAG-IDA) scheme, 134 cases) and group B (daunorubicin, cytarabine and etoposide (DAE) scheme, 55 cases). Age, gender, response rate, recurrence rate, mortality, molecular genetic characteristics and other clinical data were compared between groups. Kaplan-Meier method was used for survival analysis and survival curve was drawn. Cox regression model was used to analyze prognostic factors. Results: A total of 584 AML children were diagnosed, including 346 males and 238 females. And a total of 189 children with CBF-AML were included, including 117 males and 72 females. The age of diagnosis was 7.3 (4.5,10.0)years, and the white blood cell count at initial diagnosis was 21.4 (9.7, 47.7)×10⁹/L.The complete remission rate of the first course (CR1) of induction therapy, relapse rate, and mortality of children with CBF-AML were significantly different from those in the non-CBF-AML group (91.0% (172/189) vs. 78.0% (308/395); 10.1% (19/189) vs. 18.7% (74/395); 13.2% (25/189) vs. 25.6% (101/395), all P<0.05). In children with CBF-AML, the CBFβ-MYH11 subgroup had higher initial white blood cells and lower proportion of extramedullary invasion than the AML1-ETO subgroup, with statistical significance (65.7% (23/35) vs. 14.9% (23/154), 2.9% (1/35) vs. 16.9% (26/154), both P<0.05). AML1-ETO subgroup had more additional chromosome abnormalities (75/154), especially sex chromosome loss (53/154). Compared with group B, group A had more additional chromosome abnormalities and a higher proportion of tumor reduction regimen, with statistical significance (50.0% (67/134) vs. 29.1% (16/55), 34.3% (46/134) vs. 18.2% (10/55), both P<0.05). Significant differences were found in 5-years event free survival (EFS) rate and 5-year overall survival (OS) rate between CBF-AML group and non-CBF-AML group ((77.0±6.4)%vs. (61.9±6.7)%,(83.7±9.0)%vs. (67.3±7.2)%, both P<0.05).EFS and OS rates of AML1-ETO subgroup and CBFβ-MYH11 subgroup in children with CBF-AML were not significantly different (both P>0.05). Multivariate analysis showed in the AML1-ETO subgroup, CR1 rate and high white blood cell count (≥50×10⁹/L) were independent risk factors for EFS (HR=0.24, 95%CI 0.07-0.85,HR=1.01, 95%CI 1.00-1.02, both P<0.05) and OS (HR=0.24, 95%CI 0.06-0.87; HR=1.01, 95%CI 1.00-1.02; both P<0.05). Conclusions: In CBF-AML, AML1-ETO is more common which has a higher extramedullary involvement and additional chromosome abnormalities, especially sex chromosome loss. The prognosis of AML1-ETO was similar to that of CBFβ-MYH11. The selection of induction regimen group FLAG-IDA for high white blood cell count and additional chromosome abnormality can improve the prognosis.
Male ; Female ; Humans ; Child ; Retrospective Studies ; RUNX1 Translocation Partner 1 Protein/genetics* ; Core Binding Factor Alpha 2 Subunit/therapeutic use* ; Prognosis ; Leukemia, Myeloid, Acute/genetics* ; Cytarabine/therapeutic use* ; Oncogene Proteins, Fusion/genetics* ; Chromosome Aberrations

OBJECTIVETo study the cellular activity of asparagine synthetase in different types of childhood acute lymphoblastic leukemia (ALL).

METHODSThe cellular activity of asparagine synthetase was detected by HPLC-FLD and Protein measurement in 28 ALL children (7 cases of T-ALL and 21 cases of B-lymphoid lineage ALL) before chemotherapy.

RESULTSThe asparagines synthetase activity levels in T-ALL children were significantly higher than those of the B-lymphoid lineage ALL patients, with the median activity level of 9.3 nM Asn/mg protein/hr vs 5.2 nM Asn/mg protein/hr (P < 0.05). The distribution of the asparagine synthetase activity demonstrated a polymorphism in either T-ALL or B-lymphoid lineage ALL patients.

CONCLUSIONSThe cellular activity of asparagines synthetase in ALL patients is presented with a polymorphism distribution. The asparagines synthetase activity levels in T-ALL are significantly higher than in B-lymphoid lineage ALL.

Asparaginase ; therapeutic use ; Aspartate-Ammonia Ligase ; genetics ; metabolism ; Child ; Core Binding Factor Alpha 2 Subunit ; genetics ; Female ; Humans ; Male ; Oncogene Proteins, Fusion ; genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; enzymology ; RNA, Messenger ; analysis

Objective: To evaluate the outcomes and identify the prognostic factors of childhood acute lymphoblastic leukemia (ALL) treated with Chinese Children's Cancer Group study ALL-2015 (CCCG-ALL-2015) protocol. Methods: There were two randomization studies in CCCG-ALL-2015 study. A total of 7 640 newly diagnosed ALL patients in 20 hospitals of multi-institutional study group between January 2015 and December 2019 were treated with unified protocol. CCCG-ALL-2015 protocol featured risk-directed therapy based on morphology, immunophenotype, and genetic features, and adjusted according to minimal residual disease (MRD) assay on day 19 and day 46 of induction, which totally omitted prophylactic cranial irradiation. Two randomized controlled trails were designed. Children with Philadelphia chromosome-positive ALL (Ph⁺ALL) were randomly treated with dasatinib (Ph-D group) or imatinib (Ph-I group). During the latter half of continuation therapy, children were randomly treated with seven pulses of vincristine plus dexamethasone (group A) or not (group B). The survival rates of different groups were compared. Event-free survival (EFS) and overall survival (OS) curves were estimated according to the Kaplan-Meier method and compared by Log-rank test. Cox proportional hazards model was used for multivariate analysis. Results: Of the 7 640 enrolled patients, there were 4 521 males and 3 119 females, 7 508 (98.3%) entered complete remission. The 5-year EFS was 60.1% (95%CI 49.8%-72.5%) in the Ph-D group and 39.4% (95%CI 26.9%-57.7%) in the Ph-I group (χ²=5.00, P=0.020). Between patients with lower risk (LR) and intermediate and higher risk (I/HR) treated with (group A) or without (group B) additional pulse of vincristine plus dexamethasone, there were no difference in 5-year EFS and OS. The one-sided 95% upper confidence bound for the difference in 5-year EFS and OS were 0.02 and 0.01 for LR, 0.05 and 0.01 for I/HR, establishing non-inferiority, lower than 0.05. The follow-up time was 3.5 (2.4,4.8) years. The 5-year OS was 90.9% (95%CI 90.2%-91.7%), and EFS was 80.1% (95%CI 79.0%-81.2%). The 5-year cumulative risk of any relapse was 15.3% (95%CI 14.3%-16.3%).The cumulative risk of isolated central nervous system (CNS) relapse was 1.9% (95%CI 1.6%-2.2%), and any CNS relapse 2.7% (95%CI 2.3%-3.1%). The 5-year cumulative risk of death during remission was 1.3% (95%CI 1.0%-1.6%). In the multivariate analysis, the independent factors associated with inferior EFS of patients with B-ALL were age≥10 years, male sex, white blood cell count ≥50×10⁹/L, CNS2 or CNS3 status, BCR-ABL fusion, KMT2A rearrangements, without ETV6-RUNX1 fusion and the presence of MRD>0.01% at day 19 or 46 (all P<0.05). Among patients with T-ALL, the significant predictors for lower EFS were the BCR-ABL1 fusion and MRD≥0.10% at day 46 (both P<0.05). Conclusions: Patients treated with CCCG-ALL-2015 protocol without the use of prophylactic cranial irradiation have favorable outcomes, and the cumulative risk of isolated CNS relapse and cumulative risk of death during remission are low. Intensive chemotherapy including dasatinib yield superior results compared to imatinib in the treatment of Ph⁺ALL. Vincristine plus dexamethasone pulses can be omitted for ALL children without decrease in treatment ontcome during the latter half of continuation therapy.
Antineoplastic Combined Chemotherapy Protocols ; Child ; China/epidemiology* ; Core Binding Factor Alpha 2 Subunit ; Dasatinib/therapeutic use* ; Dexamethasone/therapeutic use* ; Disease-Free Survival ; Female ; Humans ; Imatinib Mesylate/therapeutic use* ; Male ; Neoplasm, Residual ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Prognosis ; Recurrence ; Treatment Outcome ; Vincristine/therapeutic use*

OBJECTIVETo present a special case with the karyotype and molecular marker of acute myeloid leukemia (AML)-M2 who was induced to complete remission by all-trans retinoic acid (ATRA) alone.

METHODSA recently hospitalized young female patient with acute leukemia was initially diagnosed as M3 subtype based on morphological French-American-British (FAB) classification. Karyotype analysis using standard G and R banding techniques and RT-PCR were applied to further define the diagnosis. After primarily cultured bone marrow cells from the iliac aspiration were tested for in vitro induced differentiation, the patient was treated with oral all-trans retinoic acid alone, 60 mg per day until complete remission was achieved. Peripheral blood and bone marrow changes were monitored over the whole treatment course.

RESULTSThe characteristic chromosomal aberration for M3, the t(15;17) reciprocal translocation, was not found while a t(8;21) translocation was verified. Furthermore, an amplified product of the AML-1/ETO fusion gene instead of the PML/RAR alpha fusion gene was detected by RT-PCR and the diagnosis was corrected from M3 to M2. Primary cultured bone marrow cells can be fully induced to terminal differentiation after 4 days exposure to ATRA. A hematological complete remission was achieved after 40 days treatment with ATRA as a single therapeutic agent, suggesting an alternative pathway mediating ATRA-induced myeloid differentiation.

CONCLUSIONA leukemia patient with a subtype other than M3, such as M2 in this case, may also be induced to complete remission by the mechanism of ATRA-induced terminal differentiation. This implies that there may be a pathway other than PML/RAR alpha fusion gene product which mediates ATRA-induced myeloid maturation in leukemia cells.

Adolescent ; Antineoplastic Agents ; therapeutic use ; Core Binding Factor Alpha 2 Subunit ; Female ; Humans ; Leukemia, Myeloid, Acute ; drug therapy ; genetics ; Neoplasm Proteins ; analysis ; genetics ; Oncogene Proteins, Fusion ; analysis ; genetics ; physiology ; RUNX1 Translocation Partner 1 Protein ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription Factors ; genetics ; physiology ; Tretinoin ; therapeutic use

This study was aimed to investigate the clinical characteristics of relapsed-refractory acute myeloid leukemia (AML) with AML1-ETO⁺, and its therapeutic efficacy and side effects when decitabine combined with modified CAG regimen was used. Clinical data of 5 cases of AML with AML1-ETO⁺ from January 2013 to Agust 2013 were analyzed retrospectively. The analyzed data included age, sex, initial symptoms, peripheral blood and bone marrow characteristics. Meanwhile, the therapeutic effecacy and side effects of decitabine combined with modified CAG regimen were evaluated. The 5 patients were with median age of 35 (17-43) years. Among these 5 patients, 2 patients were relapsed and other 3 patients were relapsed-refractory patients, their median white blood cell count was 12.55 (7.8-66.55) × 10⁹/L, median platelets count was 44 (20-72) × 10⁹/L, median hemoglobin level was 110 (77-128) g/L, median lactate dehydrogenase level was 312.9 U/L (123.6-877.8) at the initial diagnosis. The results showed that after decitabine combined with modified CAG regimen was administered, 4 patients achieved complete remission, 1 patient did not achieve remission, the overall remission rate was 80% (4/5). The main side effects of this regimen was myelosuppression, these were no new lung infection and other serious complications, one case without complete remission treated with FLAG once again died of heart failure when being mobilized for transplantation. It is concluded that according to preliminary results of decitabine combined with modified CAG regimen for relapsed and refractory AML patients with AML1-ETO⁺ displays higher remission rate and lower side effects, which worthy to further explore for clinal application.
Aclarubicin ; administration & dosage ; Adolescent ; Adult ; Antineoplastic Combined Chemotherapy Protocols ; administration & dosage ; therapeutic use ; Azacitidine ; administration & dosage ; analogs & derivatives ; Core Binding Factor Alpha 2 Subunit ; metabolism ; Cytarabine ; administration & dosage ; Granulocyte Colony-Stimulating Factor ; administration & dosage ; Humans ; Leukemia, Myeloid, Acute ; drug therapy ; metabolism ; Oncogene Proteins, Fusion ; metabolism ; RUNX1 Translocation Partner 1 Protein ; Recurrence ; Retrospective Studies ; Treatment Outcome ; Young Adult

The study was aimed to investigate the relation between the expression level of TEL-AML1 (translocation ETS leukemia-acute myeloid leukemia 1) fusion gene and clinical characteristics as well as early response to treatment in children with ALL (acute lymphoblastic leukemia). With real-time quantitative polymerase chain reaction (RQ-PCR), the expression level of TEL-AML1 at diagnosis and MRD (minimal residual disease) at the end of induction of remission were detected in 35 children with ALL, including 20 SR (standard risk) and 15 IR (intermediate risk) patients. The expression level of TEL-AML1 and clinical characteristics at diagnosis were compared between MRD negative and MRD positive patients. The relation between TEL-AML1 expression levels at diagnosis, MRD level and clinical characteristics as well as early response to treatment were also explored. The results indicated that the expression levels of TEL-AML1 at diagnosis were 1.63 x 10(4) copies/10(4) copies ABL (median). At the end of induction of remission, 16 patients (10 SR and 6 IR patients) did not achieve molecular remission, whose MRD levels were 0.84 - 282.93 copies/10(4) copies ABL. No relation was found between expression levels of TEL-AML1 at diagnosis and clinical characteristics as well as MRD level. There was a significant relation between MRD level and blast count in peripheral blood (PB) at day 8 after prednisone trial induction. Significant relations between MRD level and presenting leukocyte count, blast percentage in PB were also found in the patients with presenting leukocyte count < 25 x 10(9)/L. TEL-AML1 expression level at diagnosis of MRD negative patients was lower than that of MRD positive ones. It is concluded that therapy after induction of remission is of importance by the fact that 45.71% children with TEL-AML1(+) ALL did not achieve molecular remission at the end of induction of remission. The effectiveness of prednisone trial predicts the MRD level. In addition, presenting leukocyte count, blast percentage in PB and TEL-AML1 expression level at diagnosis may have an effect on MRD level to some extent.
Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Child ; Child, Preschool ; Chromosomes, Human, Pair 12 ; Chromosomes, Human, Pair 21 ; Core Binding Factor Alpha 2 Subunit ; metabolism ; Female ; Gene Fusion ; Humans ; Infant ; Male ; Oncogene Proteins, Fusion ; metabolism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; genetics ; Translocation, Genetic

OBJECTIVETo determine the incidence of TEL-AML1 fusion gene in childhood acute lymphoblastic leukemia (ALL) and to compare the clinical features between TEL-AML1 positive and negative patients.

METHODSSamples of bone marrow or peripheral blood were collected from 95 newly diagnosed ALL children and the TEL-AML1 fusion gene was detected using nested reverse transcription-polymerase chain reaction (RT-PCR). The ALL patients were stratified into TEL-AML1 positive and negative groups and the clinical features were compared.

RESULTSAmong 95 patients, 20 (21.05%) were TEL-AML1 positive. The median age of TEL-AML1 positive patients was 5.9 years old and M/F ratio was 1.22:1. There were significant differences between TEL-AML1 positive and negative patients in hepatomegaly (2.75 cm vs. 4 cm below costal arch, P=0.006), splenomegaly (0 cm vs. 3 cm below costal arch, P < 0.001), initial white blood cell count (median 7.40 x 10(9)/L vs.18.70 x 10(9)/L, P=0.011), initial peripheral blood blast (median 2.45 x 10(9)/L vs.11.66 x 10(9)/L, P=0.013), hemoglobin level [(61.45 +/- 13.46) g/L vs. (75.89 +/- 23.11) g/L, P=0.003] and serum lactate dehydrogenase [(621.47 +/- 335.85) U/L vs.(1566.64 +/- 1720.45) U/L, P=0.020], while no differences were found between two groups in age, gender ratio, initial platelet count, percentage of blast in bone marrow, immunophenotypes and the expression of myeloid antigen CD13, CD33 and CD34. The prednisone sensitivity test showed that all 12 TEL-AML1 positive patients were good responders, while there were 11 prednisone poor responders among 40 negative patients (27.50%, P < 0.05). Bone marrow examination on day 15 showed no difference in the rate of complete remission between TEL-AML1 positive and negative patients.

CONCLUSIONThe incidence of TEL-AML1 fusion gene in cases of ALL is 21.05%. The load of leukemia cells in TEL-AML1 positive patients is significantly smaller than its counterparts, and the blast cells in TEL-AML1 positive patients are more sensitive to prednisone, indicating childhood ALL with TEL-AML1 fusion gene has a favorable prognosis.

Adolescent ; Bone Marrow ; pathology ; Child ; Child, Preschool ; Core Binding Factor Alpha 2 Subunit ; genetics ; Female ; Gene Fusion ; Humans ; Infant ; Infant, Newborn ; Male ; Phenotype ; Platelet Count ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; blood ; genetics ; immunology ; pathology ; Prednisone ; therapeutic use ; Proto-Oncogene Proteins c-ets ; genetics ; RNA ; isolation & purification ; Repressor Proteins ; genetics